Current Overview of Spinocerebellar Ataxia Type 7 in Mexican Population: Challenges in Specialized Care for a Rare Disease.

Spinocerebellar ataxia type 7 (SCA7) is a rare genetic disease characterized by progressive cerebellar syndrome and macular degeneration. In a previous study, we clinically and genetically characterized a group of Mexican patients, which represented one of the largest cohorts of SCA7 patients worldwide and demonstrated that all patients had a unique genetic origin. Our laboratory developed a program for the diagnosis, medical care, and long-term follow-up of these patients living in Veracruz State, and in this report, we present an update to this research, covering 2013 to 2024. So far, we identified 172 SCA7 carriers, with a few cases outside Veracruz, and our data support that the length of the CAG repeat tract mainly determines disease severity and life expectancy, and accordingly, we define three different phenotypes, early-onset (EO), classical-onset (CO), and late-onset (LO), with EO patients showing the lowest life expectancy. Furthermore, we found that parental transmission of mutant alleles leads to increased CAG repeat instability, compared to maternal ones. Interestingly, a haplotype analysis revealed that patients outside Veracruz may have different genetic origins. In conclusion, longitudinal observations of SCA7 patients provide insight into the natural history of SCA7 and help to design strategies for diagnosis, genetic counseling, physical rehabilitation, and therapeutic alternatives.

Rare diseases: What rheumatologists need to know?

Although the terms "rare diseases" (RD) and "orphan diseases" (OD) are often used interchangeably, specific nuances in definitions should be noted to avoid misconception. RD are characterized by a low prevalence within the population, whereas OD are those inadequately recognized or even neglected by the medical community and drug companies. Despite their rarity, as our ability on discovering novel clinical phenotypes and improving diagnostic tools expand, RD will continue posing a real challenge for rheumatologists. Over the last decade, there has been a growing interest on elucidating mechanisms of rare autoimmune and autoinflammatory rheumatic diseases, allowing a better understanding of the role played by immune dysregulation on granulomatous, histiocytic, and hypereosinophilic disorders, just to name a few. This initiative enabled the rise of innovative targeted therapies for rheumatic RD. In this review, we explore the state-of-the art of rare RD and the critical role played by rheumatologists in healthcare. We also describe the challenges rheumatologists may face in the coming decades.

Facing the challenges to shorten the diagnostic odyssey: first Whole Genome Sequencing experience of a Colombian cohort with suspected rare diseases.

Exome and genome sequencing (ES/GS) are routinely used for the diagnosis of genetic diseases in developed countries. However, their implementation is limited in countries from Latin America. We aimed to describe the results of GS in patients with suspected rare genetic diseases in Colombia. We studied 501 patients from 22 healthcare sites from January to December 2022. GS was performed in the index cases using dried blood spots on filtercards. Ancestry analysis was performed under iAdmix. Multiomic testing was performed when needed (biomarker, enzymatic activity, RNA-seq). All tests were performed at an accredited genetic laboratory. Ethnicity prediction data confirmed that 401 patients (80%) were mainly of Amerindian origin. A genetic diagnosis was established for 142 patients with a 28.3% diagnostic yield. The highest diagnostic yield was achieved for pathologies with a metabolic component and syndromic disorders (p < 0.001). Young children had a median of 1 year of diagnostic odyssey, while the median time for adults was significantly longer (15 years). Patients with genetic syndromes have spent more than 75% of their life without a diagnosis, while for patients with neurologic and neuromuscular diseases, the time of the diagnostic odyssey tended to decrease with age. Previous testing, specifically karyotyping or chromosomal microarray were significantly associated with a longer time to reach a definitive diagnosis (p < 0.01). Furthermore, one out of five patients that had an ES before could be diagnosed by GS. The Colombian genome project is the first Latin American study reporting the experience of systematic use of diagnostic GS in rare diseases.

Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile.

Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the "diagnostic odyssey" for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.

Évaluation du statut de phosphorylation de STAT1 par cytométrie en flux / Evaluation of STAT1 Phosphorylation Status by Flow Cytometry

INTRODUCTION: Une demande d'introduction d'une nouvelle analyse au Répertoire québécois et système de mesure des procédures de biologie médicale (ci-après nommé Répertoire) a été transmise à l'Institut national d'excellence en santé et en services sociaux (INESSS) à travers le mécanisme d'évaluation des nouvelles analyses de biologie médicale. Le mandat vise à évaluer la pertinence d'introduire le statut de phosphorylation de la protéine STAT1 par cytométrie en flux au Répertoire. MÉTHODOLOGIE: L'évaluation a été réalisée selon l'approche basée sur l'appréciation globale de la valeur que l'Institut préconise dans son Énoncé de principes et fondements éthiques, et qui stipule qu'une intervention apporte de la valeur dans la mesure où son usage ou sa mise en place contribue à la triple finalité du système de santé et de services sociaux dans le contexte québécois. La démarche d'évaluation comprend une revue de la documentation scientifique, une recherche de la littérature grise et une consultation ad hoc menée auprès de cliniciens spécialisés en immunologie-allergologie pédiatrique et adulte. Une revue de la littérature économique a été réalisée concernant l'efficience du statut de phosphorylation de STAT1 (pSTAT1). Une analyse d'impact budgétaire considérant les coûts liés à l'ajout au Répertoire de ce test a également été réalisée. Les coûts ont été projetés sur un horizon de trois ans selon la perspective du système de soins de santé québécois. L'ensemble des données scientifiques, contextuelles et expérientielles a été interprété et apprécié à l'aide d'une approche basée sur l'appréciation globale de la valeur définie selon cinq dimensions : socioculturelle, populationnelle, clinique, organisationnelle et économique. Les constats issus de cette démarche évaluative ont servi à guider les discussions et le processus d'analyse de la Direction de l'évaluation des médicaments et des technologies à des fins de remboursement. CONTEXTE DE L'ÉVALUATION: Les erreurs innées de l'immunité (EII), précédemment appelées déficits immunitaires primaires (DIP), sont un groupe de maladies génétiques qui se manifestent entre autres par une susceptibilité accrue aux infections récurrentes, atypiques, sévères ou chroniques, aux réactions allergiques, inflammatoires ou auto-immunes, aux insuffisances médullaires et à certains cancers. Ces maladies sont monogéniques et causées par des variants germinaux pathogènes qui entraînent la perte ou le gain de fonction d'un des gènes impliqués dans les EII. Plusieurs protéines sont impliquées dans les EII, telles que celles de la voie de signalisation JAK/STAT. La famille des STAT comprend sept membres : STAT1, 2, 3, 4, 5A, 5B et 6. Une perte de fonction de STAT1 peut être responsable d'une susceptibilité accrue aux infections mycobactériennes. Les mutations activatrices de STAT1 provoquent un défaut de déphosphorylation qui se manifeste cliniquement par de la candidose mucocutanée chronique et des manifestations auto-immunes systémiques. DIMENSION SOCIOCULTURELLE: Plusieurs des sociétés savantes consultées s'étant positionnées sur le sujet recommandent le test du statut de pSTAT1 dans le diagnostic de certaines EII. Les cliniciens consultés sont aussi de cet avis. L'ajout éventuel d'un test fonctionnel comme celui de pSTAT1 est en concordance avec la Politique québécoise pour les maladies rares, Pour une meilleure reconnaissance et prise en charge des personnes atteintes de maladies rares, qui a été publiée en 2023. Cette politique vise à « optimiser l'accès à des soins et à des services de santé de qualité, sécuritaires, équitables, inclusifs et adaptés aux besoins particuliers des patients atteints de maladies rares, et culturellement sensibles ¼. Dimension populationnelle: Les trois types de dysfonctions associés à la phosphorylation de la protéine STAT1 (le gain ou la perte de fonction et la présence d'autoanticorps anti-IFN-γ neutralisants) peuvent être détectés par le test de cytométrie en flux (CMF). Le traitement des dysfonctions de STAT1 inclut principalement des combinaisons d'antifongiques ou d'antibiotiques souvent à long terme, des greffes de cellules souches hématopoïétiques (GCSH) et des inhibiteurs de la voie JAK/STAT. L'ajout du test de pSTAT1 au Répertoire contribuerait à la prise en charge rapide des patients et aiderait au choix de traitement, limitant ainsi l'errance médicale de ces patients. De plus, il permettrait de promouvoir la disponibilité du test et de standardiser les résultats obtenus. DIMENSION CLINIQUE: Afin de documenter la validité et l'utilité clinique du test, huit articles ont été retenus, soit six documents sur les pertes et les gains de fonction de STAT1 et deux articles sur la présence d'autoanticorps anti-IFN-γ. Les données montrent que l'évaluation du statut de pSTAT1 contribue à détecter les défauts de la boucle d'amplification IL-12/IFN-γ, à valider les anomalies fonctionnelles de STAT1 et à identifier la présence d'autoanticorps neutralisants anti-IFN-γ chez les patients cliniquement suspectés de certaines EII. Il sert également à évaluer la fonctionnalité des variants de signification incertaine (VSI) obtenus après des analyses génétiques et aide à cibler les investigations génétiques. Enfin, certaines données montrent que le test pSTAT1 améliore la prise en charge des patients, notamment en ce qui concerne le recours à l'antibioprophylaxie, à l'immunomodulation ou à la GCSH. DIMENSIONS ORGANISATIONNELLE ET ÉCONOMIQUE: Le test de pSTAT1 est offert par la grappe Montréal-CHU Sainte-Justine depuis 2014. Il a été effectué entre 2014 et 2023 sous un code générique qui regroupe tous les tests de CMF associés à une valeur pondérée inférieure à celle estimée du test pSTAT1. Le laboratoire demandeur mentionne avoir la capacité d'effectuer la totalité des analyses pour couvrir les besoins de toute la province et de faire face à une augmentation de la volumétrie, le cas échéant. Selon les cliniciens consultés, la réalisation du test localement apporterait un gain de temps et un soutien pour l'interprétation des résultats. L'accès à d'autres tests comme celui du dosage de l'IL-12 devrait demeurer disponible via les envois hors Québec pour couvrir des besoins exceptionnels. Une réponse sera obtenue en 24 à 36 heures; ce délai est jugé adéquat par les cliniciens consultés. L'efficience de l'analyse proposée ne peut être évaluée justement compte tenu du fait que les issues cliniques et les coûts ne peuvent être adéquatement mesurés ou approximés. Toutefois, l'introduction de l'analyse proposée au Répertoire devrait engendrer des économies d'environ 132 000 $ au cours des trois premières années. Bien que le coût de cette analyse ne puisse être justifié par des écrits scientifiques ou une évaluation robuste, aucun signal n'indique que son utilisation, spécifique au contexte de certaines EII, pourrait constituer une utilisation non responsable des ressources. Le risque économique de son introduction est considéré comme très faible. CONCLUSIONS: À la lumière des constats formulés ci-dessus, l'INESSS recommande l'introduction de l'analyse portant sur l'évaluation du statut de phosphorylation de STAT1 par cytométrie en flux au Répertoire, étant donné que: cette analyse est recommandée par les sociétés savantes et les cliniciens spécialisés dans le diagnostic de certaines erreurs innées de l'immunité; la littérature scientifique montre que le test permet la détection des dysfonctions de STAT1 et la vérification de la fonctionnalité des VSI. Il aide à la prise en charge adéquate des patients, afin de diminuer l'errance diagnostique souvent observée avec les maladies rares et d'offrir un traitement approprié rapidement; l'analyse est disponible depuis plus de dix années dans le réseau québécois de la santé et des services sociaux; le recours à l'analyse dans le contexte des EII constituerait une utilisation responsable des ressources; e risque économique de l'inscription de l'analyse au Répertoire est considéré comme étant très faible. Le ou les laboratoires désignés devront satisfaire aux exigences de la norme ISO 15189.

INTRODUCTION: The Institut national d'excellence en santé et en services sociaux (INESSS) has received a request to introduce a new assay to the Répertoire québécois et système de mesure des procédures de biologie médicale (hereinafter referred to as the Répertoire), through the evaluation mechanism for new medical biology assays. The mandate is to evaluate the relevance of introducing the phosphorylation status of the STAT1 protein by flow cytometry into the Répertoire. METHODOLOGY: The evaluation was conducted according to the overall value assessment approach advocated by the Institute in its Statement of Ethical Principles and Foundations, which stipulates that an intervention brings value insofar as its use or implementation contributes to the triple aim of the health and social services system in Quebec. The evaluation process included a review of the scientific literature, a grey literature search and an ad hoc consultation with clinicians specializing in pediatric and adult immunologyallergology. A review of the economic literature was conducted on the efficiency of STAT1 phosphorylation status (pSTAT1). A budget impact analysis was also conducted, considering the costs associated with adding this test to the Répertoire. Costs were projected over a three-year horizon from the perspective of the Quebec healthcare system. All scientific, contextual, and experiential data were interpreted and assessed using an approach based on an overall value assessment defined according to five dimensions: sociocultural, population-based, clinical, organizational, and economic. The findings of this evaluative approach were used to guide the discussions and analysis process of the Direction de l'évaluation des médicaments et des technologies à fins de remboursement. EVALUATION CONTEXT: Inborn errors of immunity (IEIs), previously known as primary immune deficiencies (PIDs), are a group of genetic diseases manifested by, among other things, increased susceptibility to recurrent, atypical, severe, or chronic infections, allergic, inflammatory, or autoimmune reactions, bone marrow failure and certain cancers. These diseases are monogenic and caused by pathogenic germline variants that result in the loss or gain of function of one of the genes involved in IEIs. Several proteins are involved in IEIs, such as those of the JAK/STAT signaling pathway. The STAT family comprises seven members: STAT1, 2, 3, 4, 5A, 5B and 6. Loss of STAT1 function may be responsible for increased susceptibility to mycobacterial infections. Activating mutations in STAT1 cause a dephosphorylation defect that manifests clinically as chronic mucocutaneous candidiasis and systemic autoimmune manifestations. Socio-Cultural Dimension: Several of the learned societies consulted on this subject recommend testing for pSTAT1 status in the diagnosis of certain IEIs. The clinicians consulted also share this opinion. The possible addition of a functional test such as pSTAT1 is in line with the Politique québécoise pour les maladies rares, Pour une meilleure reconnaissance et prise en charge des personnes atteintes de maladies rares, published in 2023. This policy aims to "optimize access to quality health care and services that are safe, equitable, inclusive, and adapted to the specific needs of culturally sensitive patients with rare diseases." Population Dimension: The three types of dysfunctions associated with phosphorylation of the STAT1 protein (gain or loss of function and the presence of neutralizing anti-IFN-γ autoantibodies) can be detected by flow cytometry testing. Treatment of STAT1 dysfunction mainly includes often long-term combinations of antifungals or antibiotics, hematopoietic stem cell transplantation (HSCT), and inhibitors of the JAK/STAT pathway. The addition of the pSTAT1 test to the Répertoire would contribute to the rapid management of patients and help in the choice of treatment, thus limiting medical wandering for these patients. It would also promote the availability of the test and standardize the results obtained. Clinical Dimension: In order to document the validity and clinical utility of the test, eight papers were selected: six papers on loss and gain of function of STAT1 and two papers on the presence of antiIFN-γ autoantibodies. The data show that evaluation of pSTAT1 status helps to detect defects in the IL-12/IFN-γ amplification loop, validate STAT1 functional abnormalities and identify the presence of neutralizing anti-IFN-γ autoantibodies in patients clinically suspected of certain IEIs. It is also used to assess the functionality of variants of uncertain significance (VUSs) obtained after genetic analysis and helps target genetic investigations. Finally, there is some evidence that pSTAT1 improves patient management, particularly regarding the use of antibiotic prophylaxis, immunomodulation, or HSCT. Organizational and Economic Dimensions: The pSTAT1 test has been offered by the Montreal-CHU Sainte-Justine laboratories since 2014. It was performed between 2014 and 2023 under a generic code that groups together all flow cytometry tests associated with a weighted value lower than that estimated for the pSTAT1 test. The applicant laboratory states that it has the capacity to perform all the tests to cover the needs of the entire province, and to cope with any increase in volume. According to the clinicians consulted, performing the test locally would save time and provide support in interpreting results. Access to other tests, such as the IL-12 assay, should remain available via shipments outside Quebec to cover exceptional needs. A response will be obtained within 24 to 36 hours; this timeframe is deemed adequate by the clinicians consulted. The efficiency of the proposed analysis cannot be accurately evaluated, as clinical outcomes and costs cannot be adequately measured or approximated. However, the introduction of the proposed analysis to the Répertoire is expected to generate savings of approximately $132,000 over the first three years. Although the cost of this analysis cannot be justified by scientific literature or robust evaluation, there are no indications that its use, specific to the context of certain IEIs, might constitute an unaccountable use of resources. The economic risk of its introduction is considered very low. CONCLUSIONS: Considering the above findings, the INESSS recommends the introduction of the analysis of STAT1 phosphorylation status by flow cytometry to the Répertoire, given that: This analysis is recommended by learned societies and clinicians specializing in the diagnosis of certain innate immune errors; the scientific literature shows that the test enables detection of STAT1 dysfunction and verification of VUS functionality. It helps to ensure that patients are properly managed, so as to reduce the diagnostic wandering often observed with rare diseases, and to offer appropriate treatment rapidly; analysis has been available for over ten years in the Quebec health and social services network; the use of analysis in the context of IEIs would be a responsible use of resources; the economic risk of listing the analysis in the Répertoire is considered to be very low. The designated laboratory(ies) must meet ISO 15189 requirements.

[Rare diseases and undiagnosed diseases: advances in neurodevelopment]. / Enfermedades sin diagnóstico y enfermedades raras: avances en neurodesarrollo.

Rare diseases and undiagnosed diseases have recently positioned themselves as clinical entities that provide important opportunities to advance our understanding of gene functions and the impact of them in the individual development. In this review, we present how efforts made over years to understand common diseases, rare diseases and even undiagnosed diseases come together today to cooperatively advances scientific knowledge. These advance in science and new acquired knowledge, make possible to apply the advances obtained in a group of clinical conditions to others with similar phenotypic characteristics or vice versa. The cooperative work of multidisciplinary teams and the communication between clinicians and researchers have and will provide opportunities for better treatments for patients and families across multiple common and rare diseases.

Las enfermedades raras y enfermedades sin diagnóstico se han posicionado en los últimos años como condiciones clínicas que han permitido avanzar el entendimiento de las funciones de los genes y el impacto en el desarrollo del individuo. En esta revisión, presentamos como los esfuerzos individuales hechos por muchos años para entender la fisiopatología de enfermedades comunes, enfermedades raras y otras aún más raras, como las enfermedades sin diagnóstico, que se unen hoy para, de manera cooperativa, avanzar en el conocimiento científico. Estos avances en el conocimiento permiten aplicar los avances obtenidos en un grupo de condiciones clínicas a otras con características fenotípicas similares o viceversa. El trabajo conjunto de equipos multidisciplinarios y la comunicación entre clínicos e investigadores proporcionarán oportunidades para proveer mejores oportunidades de tratamiento para pacientes y familias a lo largo de múltiples diagnósticos comunes o raros.

Availability of Genetic Tests in Public Health Services in Brazil: Data from the Brazilian Rare Diseases Network.

INTRODUCTION: The Brazilian Policy for Comprehensive Care for People with Rare Diseases (BPCCPRD) was published in 2014, accrediting several reference centers and incorporating many genetic tests for the diagnosis of rare diseases (RDs). The Brazilian Network of Rare Diseases (RARAS) comprises more than 40 institutions that offer diagnosis and treatment for RDs in Brazil. This network includes Reference Services for Rare Diseases (RDRS), Reference Services for Newborn Screening (NSRS), and University Hospitals distributed in all Brazilian regions. OBJECTIVE: The aim of the study was to map the availability and distribution of the BPCCPRD diagnostic procedures in the Brazilian Unified Health System through RARAS. METHOD: Data were collected through a questionnaire on the Research Electronic Data Capture platform, with 22 questions regarding the availability of procedures. Thirty-seven coordinators from RARAS participating centers received the questionnaire link for participation by email from August/2020 to March/2021. All participating institutions ethically approved this project. RESULTS: Of the 37 institutions, 23 (62.16%) offered cytogenetic tests, 20 (54.05%) offered molecular procedures, and 22 (59.46%) offered inborn errors of metabolism diagnostic tests. The Southern blot analysis, enzyme assays on cultured tissue and urinary organic acid tests had the highest outsourcing rate. On the other hand, the procedures most frequently performed on-site were bone marrow karyotype and long-term cultured karyotype. It was observed that 10 of the 37 centers (27%) did not provide access to investigated procedures (on-site or outsourced). The North and Midwest regions stood out in terms of the unavailability of such techniques in at least 40% of the evaluated institutions. DISCUSSION AND CONCLUSION: This study reveals large discrepancies in the supply of diagnostic procedures in the Brazilian territory. Moreover, there is a broad collaboration between services through the outsourcing of multiple diagnostic techniques to address this issue. Finally, this work corroborates the importance of mapping services for the diagnosis and treatment of individuals with RDs to propose actions for the better supply and distribution of these procedures.

Challenges and recommendations to increasing the use of exome sequencing and whole genome sequencing for diagnosing rare diseases in Brazil: an expert perspective.

Early diagnosis of genetic rare diseases is an unmet need in Brazil, where an estimated 10-13 million people live with these conditions. Increased use of chromosome microarray assays, exome sequencing, and whole genome sequencing as first-tier testing techniques in suitable indications can shorten the diagnostic odyssey, eliminate unnecessary tests, procedures, and treatments, and lower healthcare expenditures. A selected panel of Brazilian experts in fields related to rare diseases was provided with a series of relevant questions to address before a multi-day conference. Within this conference, each narrative was discussed and edited through numerous rounds of discussion until agreement was achieved. The widespread adoption of exome sequencing and whole genome sequencing in Brazil is limited by various factors: cost and lack of funding, reimbursement, awareness and education, specialist shortages, and policy issues. To reduce the burden of rare diseases and increase early diagnosis, the Brazilian healthcare authorities/government must address the barriers to equitable access to early diagnostic methods for these conditions. Recommendations are provided, including broadening approved testing indications, increasing awareness and education efforts, increasing specialist training opportunities, and ensuring sufficient funding for genetic testing.

Esclerodermia e Polimiosite em paciente evoluindo com calcinose severa: um relato de caso / Scleroderma and Polymyositis in a patient developing severe calcinosis: a case report

Introdução: As Doenças doTecido Conjuntivo são um grupo de doenças autoimunes ou idiopáticas, crônicas, de acometimento geralmente sistêmico e que podem, ou não, atacar o indivíduo de forma concomitante. O presente relato de caso apresenta a descrição de Esclerose Sistêmica e Polimiosite em uma mesma paciente. O fenômeno é conhecido como Sindrome de Overlap (presença simultânea de duas ou mais doenças do tecido conjuntivo, de natureza auto-imune em um paciente) e considerado raro. A Polimiosite e Dermatomiosite são doenças idiopáticas inflamatórias crônicas que afetam a musculatura estriada, a pele e outros órgãos. Esclerose sistêmica é outra doença não tão frequente, extremamente incapacitante pela sua repercussão multissistêmica, de evolução crônica e progressiva. As calcinoses, assim como fenômeno de Raynaud, mialgia, disfagia e queixas respiratórias, podem estar presentes em ambas as patologias, e no caso relatado não foi diferente.Métodos:Oestudo observacional descritivo relata o caso de uma paciente atendida pelo setor de reumatologia do Hospital do Servidor Público Municipal de São Paulo (HSPM), reunindo informações contidas em prontuários, do ano de 2014 até o presente momento. Discussão: A Dermatomiosite e a Síndrome de CREST, subtipos da esclerose sistêmica e das Miosites Inflamatórias, respectivamente, são doenças raras e de difícil diagnóstico devido a presença se sintomas em comum e passíveis de serem encontrados em outras comorbidades não auto-imunes. Seu tratamento é feito com imunossupressores e medicações voltadas para cada queixa clínica do paciente, a depender de uma boa investigação clínica e critérios diagnósticos fechados, evitando progressão acelerada e complicações clínicas. Conclusão: O tratamentoproposto para Esclerose sistêmica e Dermatomiosite já possui uma gama extensa de possibilidades farmacológicas e não-farmacológicas mas ainda sem protocolos específicos consensuais, sendo indicadas de acordo com a experiência pessoal do profissional, visando diminuição dos processos inflamatórios, recuperação de qualidade de vida e prevenção de complicações. Já o tratamento das calcinoses ainda não apresenta resultados satisfatórios, sendo propostos de acordo com a resposta clínica individual dos pacientes. Palavras-chave: Esclerose. Polimiosite. Dermatomiosite. Calcinose. Síndrome CREST.

Terminal deletion of the short arm of chromosome 6 (6P25 3P 243): a literature review and case report of a Brazilian child / Deleção terminal do braço curto do cromossomo 6 (6p25 3p 243): uma revisão de literatura e relato de caso de uma criança brasileira

Introduction: Deletion syndromes are rare events in clinical practice. A chromosomal deletion occurs when seg-ments of genetic information are missing on a particular chromosome or more. The absence of some genes implies varied phenotypes, which detailed explanation is not fully elucidated yet. Objective: Report the case of a child with a terminal segment deletion of 8,9 Mb on the short arm of chromosome 6 (in 6p25.3p24.3) Methods: This case report was approved by the Ethics and Research Committee of the institution. For its preparation, the exam data provided by the patient's family were added from prenatal to early childhood and the discussion with professionals related to the case. Results: B.A.G., a two-year-old female child, the only daughter of non-consanguineous par-ents, no family history of similar diseases. She was born by premature cesarean section (GA: 35 weeks), presenting Dandy-Walker malformation, Fallot tetralogy, head circumference in the 97th percentile, and syndromic facies, with hypertelorism, low implantation of the ears, and opacity of both lenses. Conclusion: Deletions on chromosome 6 are a very rare genetic alteration. Until 2004, there were only 43 cases in the medical literature, excluding ring chromosome 6 anomalie31. Regarding the terminal deletions of the short arm, this case specifically - 6p24pter - was associated with developmental delay, brain malformations, abnormalities in the anterior chamber of the eye, hearing loss, and abnormalities in the ear, micrognathia, and heart diseases (AU)

Introdução: As síndromes de deleção são eventos raros na prática clínica. A deleção cromossômica ocorre quando segmentos de informação genética são perdidos em um ou mais cromossomos. A ausência de alguns genes implica em fenótipos variados, cuja explicação detalhada ainda não está totalmente elucidada. Objetivo: Relatar o caso de uma criança com deleção de segmento terminal de 8,9 Mb do braço curto do cromossomo 6 (em 6p25.3p24.3) Métodos: Esse relato de caso foi aprovado pelo Comitê de Ética e Pesquisa da Instituição. Para sua elaboração, foram adicionados os dados de exames fornecidos pela família do paciente desde o pré-natal até a primeira infância e a discussão com profissionais relacionados ao caso. Descrição do Caso: B.A.G., criança de dois anos, sexo femi-nino, filha única de pais não consanguíneos, sem antecedentes na família de doenças similares. Nasceu por cesárea prematura (IG 35 semanas), apresentando Síndrome de Dandy-Walker, tetralogia de Fallot, perímetro cefálico no percentil 97 e fácie sindrômica, com hipertelorismo, baixa implantação das orelhas e opacidades do cristalino bi-lateralmente. Conclusão: As deleções no cromossomo 6 são alterações genéticas de grande raridade. Até 2004, existiam apenas 43 casos na literatura médica, excluindo a anomalia do cromossomo 6 em anal 31. No que se refere às deleções terminais do braço curto, a do caso em questão - 6p24-pter - foram associadas o atraso no desenvol-vimento, malformações cerebrais, anormalidades na câmara anterior do olho, perda auditiva, anormalidades no ouvido, micrognatia e cardiopatias (AU)

Brazilian consensus recommendations for the diagnosis, screening, and treatment of individuals with fabry disease: Committee for Rare Diseases - Brazilian Society of Nephrology/2021.

Fabry disease (FD) is an X-linked inherited disorder caused by mutations in the GLA gene encoding enzyme alpha-galactosidase A (α-Gal A). The purpose of this study was to produce a consensus statement to standardize the recommendations concerning kidney involvement in FD and provide advice on the diagnosis, screening, and treatment of adult and pediatric patients. This consensus document was organized from an initiative led by the Committee for Rare Diseases (Comdora) of the Brazilian Society of Nephrology (SBN). The review considered randomized clinical trials, real-world data studies, and the expertise of its authors. The purpose of this consensus statement is to help manage patient and physician expectations concerning the outcomes of treatment. Our recommendations must be interpreted within the context of available evidence. The decisions pertaining to each individual case must be made with the involvement of patients and their families and take into account not only the potential cost of treatment, but also concurrent conditions and personal preferences. The Comdora intends to update these recommendations regularly so as to reflect recent literature evidence, real-world data, and appreciate the professional experience of those involved. This consensus document establishes clear criteria for the diagnosis of FD and for when to start or stop specific therapies or adjuvant measures, to thus advise the medical community and standardize clinical practice.

Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease.

BACKGROUND: Rare diseases are pathologies that affect less than 1 in 2000 people. They are difficult to diagnose due to their low frequency and their often highly heterogeneous symptoms. Rare diseases have in general a high impact on the quality of life and life expectancy of patients, which are in general children or young people. The advent of high-throughput sequencing techniques has improved diagnosis in several different areas, from pediatrics, achieving a diagnostic rate of 41% with whole genome sequencing (WGS) and 36% with whole exome sequencing, to neurology, achieving a diagnostic rate between 47 and 48.5% with WGS. This evidence has encouraged our group to pursue a molecular diagnosis using WGS for this and several other patients with rare diseases. RESULTS: We used whole genome sequencing to achieve a molecular diagnosis of a 7-year-old girl with a severe panvascular artery disease that remained for several years undiagnosed. We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. Bioinformatic analyses propose these mutations as the most likely cause of the disease, according to its frequency, in silico predictors, conservation analyses, and effect on the protein product. Additionally, we confirmed one mutation in each parent, supporting a compound heterozygous status in the child. CONCLUSIONS: In general, we think that this finding can contribute to the use of whole genome sequencing as a diagnosis tool of rare diseases, and in particular, it can enhance the set of known mutations associated with different diseases.

Hybrid Materials Based on Magnetic Iron Oxides with Benzothiazole Derivatives: A Plausible Potential Spectroscopy Probe.

Rare diseases affect a small part of the population, and the most affected are children. Because of the low availability of patients for testing, the pharmaceutical industry cannot develop drugs for the diagnosis of many of these orphan diseases. In this sense, the use of benzothiazole compounds that are highly selective and can act as spectroscopy probes, especially the compound 2-(4'-aminophenyl)benzothiazole (ABT), has been highlighted. This article reports the design of potential contrast agents based on ABT and iron to develop a new material with an efficient mechanism to raise the relaxation rate, facilitating diagnosis. The ABT/δ-FeOOH hybrid material was prepared by grafting (N-(4'-aminophenyl) benzothiazole-2-bromoacetamide) on the surface of the iron oxyhydroxide particles. FTIR spectra confirmed the material formations of the hybrid material ABT/δ-FeOOH. SEM analysis checked the covering of nanoflakes' surfaces in relation to the morphology of the samples. The theoretical calculations test a better binding mode of compound with iron oxyhydroxide. Theoretical findings show the radical capture mechanism in the stabilization of this new material. In this context, Fe3+ ions are an electron acceptor from the organic phase.

Appendiceal hernia: an extremely rare condition.

Appendix-associated hernias are extremely rare. They have been described sporadically in the literature, mostly as inguinal hernias. Appendix-associated incisional hernias are even more unusual. High clinical awareness is needed as complications can arise if misdiagnosis or delay occurs. We present an 80-year-old man with acute appendicitis in an incisional hernia. After successful surgery, the patient made a full recovery.

Terahertz Spectroscopy Applied to Diagnostics in Public Health: A Review

Abstract Terahertz (THz) spectroscopy is an emerging technology that is that is bringing a number of technical breakthroughs in several scientific applications. This review aimed to describe potential applications of THz spectroscopy at the biochemistry and molecules detection for food industry, environment monitoring and diagnostics, and present the importance of such technological platform in disease control and Public Health.